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Bendamustine pharmaceutical compositions

Active Publication Date: 2006-07-20
CEPHALON LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0037] Still another embodiment of the invention is a bendamustine pre-lyophilization solution or dispersion comprising one or more organic solvents where the solution or dispersions include at least one stabilizing concentration of an organic solvent which reduces the level of degradation of bendamustine so that the amount of

Problems solved by technology

Because of their high reactivity in aqueous solutions, nitrogen mustards are difficult to formulate as pharmaceuticals and are often supplied for administration in a lyophilized form that requires reconstitution, usually in water, by skilled hospital personal prior to administration.
The finished lyophilisate is unstable when exposed to light.
The reconstitution of the present bendamustine lyophilized powder is difficult.
Besides being burdensome and time-consuming for the healthcare professional responsible for reconstituting the product, the lengthy exposure of bendamustine to water during the reconstitution process increases the potential for loss of potency and impurity formation due to the hydrolysis of the product by water.

Method used

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  • Bendamustine pharmaceutical compositions
  • Bendamustine pharmaceutical compositions
  • Bendamustine pharmaceutical compositions

Examples

Experimental program
Comparison scheme
Effect test

example 1

HPLC Procedures

Method 1

Mobile Phase A: 0.1% TFA; H2O

Mobile Phase B: 0.1% TFA; 50% ACN:50% H2O

UV: 230 nm

Flow rate: 1.0 mL / min

Column temp.: 30° C.

Column: Zorbax SB-C18 5 μm 80 Å 4.6×250 mm

Sample temp.: 5° C.

Injection Volume: 10 μL

Sample Concentration: 0.25 mg / mL in MeOH

Gradient: 20% B for 1 min

[0124] 20-90% B in 23 min

[0125] 90% B for 6 min

[0126] back to 20% B in 1 min

[0127] hold at 20% B for 4 min

Run time: 30 min

Post run time: 5 min

Method 2

Mobile Phase A: 0.1% TFA; H2O:ACN (9:1)

Mobile Phase B: 0.1% TFA; H2O:ACN (5:5)

UV: 230 nm

Flow rate: 1.0 mL / min

Column: Zorbax SB-C18 5 μm 80 Å 4.6×250 mm

Column temp.: 30° C.

Sample temp.: 5° C.

Injection Volume: 10 μL

Sample Concentration: 0.25 mg / mL in MeOH

Gradient: 0% B for 3 min

[0128] 0-50% B in 13 min

[0129] 50-70% B in 17 min

[0130] 70-90% B in 2 min

[0131] 90% B for 5 min

[0132] back to 0% B in 1 min

[0133] hold at 0% B for 4 min

Run time: 40 min

Post run time: 5 min

Method 3

Phase A: HPLC g...

example 2

Solubility

[0142] The solubility of bendamustine HCl (bendamustine) in water (alone) and with varying amounts of methanol, ethanol, propanol, isopropanol, butanol and tertiary-butyl alcohol (TBA) was determined by visual inspection. Amounts of bendamustine at 15 mg / mL, mannitol at 25.5 mg / mL were prepared in 10 mL of the indicated alcohol solutions (Table 1) at room temperature. Samples were then refrigerated at 5° C. and inspected after 0, 3, 6 and 24 hours for particulates and / or precipitates.

[0143] Results summarized in Table 1 indicate that bendamustine solubility is dependant on temperature and the amount of alcohol in aqueous solutions. For all alcohols the solubility of bendamustine increased as the concentration of alcohol increased. The formation of a precipitant was also dependent on the temperature and time.

[0144] The solubility of bendamustine was also determined in 20% (v / v) TBA containing 25.5 mg / mL mannitol in water, and 30% (v / v) TBA containing 25.5 mg / mL mannitol ...

example 3

Stability

A. Stability in Water

[0147] Solutions of bendamustine (15 mg / mL), and mannitol (25.5 mg / mL) were prepared in water at room temperature and immediately placed in an ice bath (to lower the temperature quickly to about 5° C.) for 10 minutes and then refrigerated at 5° C. A sample of each formulation was analyzed by HPLC using the methods described herein after 0, 3, 6 and 24 hours when stored at 5° C.

B. Stability in Alcohols

[0148] Solutions containing 15 mg / mL bendamustine, 25.5 mg / mL mannitol, and 1.9%, 5%, 10%, 20% or 30% (v / v) ethyl alcohol in water or 5%, 10%, 20% or 30% (v / v) TBA, methanol, propanol, iso-propanol, or butanol in water were prepared at room temperature, placed into an ice bath for 10 minutes and then refrigerated at 5° C. A sample of each formulation was analyzed by HPLC after 0, 3, 6 and 24 hours when stored at 5° C.

C. Stability Results

[0149] Table 3 shows the stability results of bendamustine in water with no addition of alcohol over a 24 hour pe...

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Abstract

The present invention provides pharmaceutical formulations of lyophilized bendamustine suitable for pharmaceutical use. The present invention further provides methods of producing lyophilized bendamustine. The pharmaceutical formulations can be used for any disease that is sensitive to treatment with bendamustine, such as neoplastic diseases.

Description

FIELD OF THE INVENTION [0001] The present invention pertains to the field of pharmaceutical compositions for the treatment of various disease states, especially neoplastic diseases and autoimmune diseases. Particularly, it relates to pharmaceutical formulations comprising nitrogen mustards, particularly the nitrogen mustard bendamustine, e.g., bendamustine HCl. BACKGROUND OF THE INVENTION [0002] The present invention claims the benefit of and priority to U.S. Ser. No. 60 / 644,354, filed Jan. 14, 2005, entitled, “Bendamustine Pharmaceutical Compositions,” which is incorporated herein by reference in its entirety, including figures and claims. [0003] The following description includes information that may be useful in understanding the present invention. It is not an admission that any such information is prior art, or relevant, to the presently claimed inventions, or that any publication specifically or implicitly referenced is prior art. [0004] Because of their high reactivity in aqu...

Claims

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Application Information

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IPC IPC(8): A61K31/4184A61K9/00
CPCA61K9/0019A61K47/10A61K31/4184A61K9/19A61P17/02A61P19/02A61P25/00A61P29/00A61P35/00A61P35/02A61P37/00A61P37/06A61K9/10
Inventor BRITTAIN, JASON EDWARDFRANKLIN, JOE CRAIG
Owner CEPHALON LLC
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